P560: ANALYSIS OF GENE MUTATION SPECTRUM AND CORRELATION BETWEEN GENETIC ABNORMALITIES IN 207 PATIANTS WITH T(8; 21) AML
Authors: Y. Nie, Y. Li, H. Zhang, H. Li, J. Zhang, C. Wang, Z. Chen, S. Yang, Y. Lin, K. Ru
Journal: HemaSphere (2022)

Background: The core binding factor (CBF) involves a subgroup of AML which is composed of a and b subunits encoded by RUNX1(AML1) and CBFβ genes respectively, and CBF is responsible for regulating multiple hematopoietic genes of myeloid differentiation. AML with abnormal CBF accounts for 12%-15% of adult AML, including t(8;21)(q22;q22) and inv (16)(p13q22), which produce RUNX1-RUNX1T1 (also known as AML1-ETO) and CBFβ-MYH11 fusion gene respectively. Next generation sequencing(NGS) revealed that AML with t (8; 21) had other somatic gene mutations at the same time. In addition to the known genetic abnormalities of RAS and tyrosine kinase signaling pathways, the genes such as epigenetic regulation showed recurrent genetic abnormalities. Some of these gene abnormalities, such as KIT, JAK2 and FLT3-ITD mutations, have been reported in many studies and result in poor prognosis. However, due to the relatively small sample or detected genes size, there are some differences in the research conclusions. This study analyzed the molecular correlation test results of 207 patients with t (8; 21) AML, and conducted a comprehensive retrospective analysis by 56 gene targeted sequencing, so as to clarify the gene distribution and related pathways involved in t (8; 21) AML patients in Chinese population, as well as the correlation between different gene mutations and chromosome abnormalities. Aims: To evaluate the gene mutational profile and its correlation with chromosomal abnormalities in acute myeloid leukemia (AML) patients with t (8; 21). Methods: The data of 207 patients with t(8;21) AML was retrieved from Sino-us diagnostics lab from June 2015 to October 2021. We analyzed the gene mutational spectrum and characterized the pathways of 56 AML-associated genes by NGS technology. Results: Among these 207 patients with t(8;21) AML, the incidence of KIT(53%) gene mutation was the highest, followed by NRAS (18%), ASXL2 (17%), FLT3 (12%), and EZH2 (10%). Most mutations were enriched in signal transduction, chromatin modification, and transcriptional regulation pathways. According to their median VAF, we found that DNA methylation genes, such as IDH1(50.8%), IDH2(49.0%), TET2 (43.8%) and DNMT3A (37.2%) or Chromatin remodeling genes, like ASXL1 (42.1%), ASXL2 (37.3%) are present in the majority of the cells. Meanwhile, alterations in RAS/RTK signaling genes like FLT3 (23.1%), KIT (32.5%) and the RAS GTPases NRAS (8.6%) and KRAS (13.3%) have the lower VAF. In addition, most KIT mutations (121/154) were located in exon 17, mainly on the SNV with D816 or N822. According to the correlation analysis, we found that IDH1/2 and complex karyotype (CK) or ZBTB7A mutation, ASXL2 and CCND2 mutation, t (x; 8; 21) abnormality and JAK2 or FLT3 mutation may co-mutate. On the contrary, KIT and NRAS mutation were mutually exclusive. Image:Summary/Conclusion: From the patients with t(8;21) AML, most gene mutations occurred in pathways involving signal transduction, chromatin modification, or transcriptional regulation. DNA methylation or Chromatin remodeling genes may occur in the early stage of leukemogenesis while RAS/RTK signaling genes may indicated later events. The coexistence or mutual exclusion between genes and chromosomes may provide a basis for further definitive diagnosis and therapeutic regimen.